All ETDs from UAB

Advisory Committee Chair

Greg M Cooper

Advisory Committee Members

Greg Barsh

Jake Chen

Robert Kimberly

Robin Lorenz

Document Type

Dissertation

Date of Award

2019

Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine

Abstract

The ability to quickly and accurately catalog an individual's genetic variation through genome sequencing has ignited a new era of diagnostic and therapeutic development for heritable disease. Although genome sequencing can provide a molecular diagnosis in a significant number of patients with suspected genetic disease, there remain a number of unsolved cases for which no pathogenic cause can be determined. This uncertainty can create a "diagnostic odyssey" in which sequential tests fail to provide a diagnostic resolution and can often delay beneficial treatment, impact family planning, and be emotionally challenging for patients and their families. Clearly, there is an unmet need to further characterize variation underlying genetic disease. In this work, we first describe how genome sequencing, worldwide collaboration, and functional biochemical characterization have lead to the discovery of a novel disease gene, RALA, causing syndromic developmental delay and intellectual disability (DD/ID). Next, we show how an analysis of Mobile Element Insertions (MEIs) from genome sequencing data in a large DD/ID cohort lead to the discovery of a de novo Alu insertion in CTNNB1. These studies provide insight into previously unknown mechanisms causing developmental disorders, and highlight how genomic data can be leveraged to advance scientific understanding and improve diagnostic and therapeutic outcomes.

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